Derivatives of lincomycin and its analogs and process

ABSTRACT

Alkyl 7-deoxy-7-RSn- Alpha -thiolincosaminides useful as intermediates for preparing antibacterially active 7-deoxy-7-RSnlincomycins are prepared by heating alkyl N-acyl-6,7-aziridino-6deamino-7-deoxy- Alpha -thiolincosaminides with an aliphatic, cycloaliphatic, or aromatic acyclic sulfide (mono, di, tri or tetrasulfide) in the presence of glacial acetic acid or other anhydrous lower alkanoic acid, or anhydrous benzoic acid or other arenoic acid of not more than 12 carbon atoms.

United States Patent [191 Bannister DERIVATIVES or LINCOMYCIN AND ITSANALOGS AND PROCESS [75] Inventor:

[73] Assignec: The Upjohn Company, Kalamazoo,

Mich.

Brian Bannister, Kalamazoo, Mich.

[ Notice: The portion of the term of this patent subsequent to Feb. 5,1991 has been disclaimed.

[22] Filed: June 18, 1973 [21] Appl. No.: 370,603

Related US. Application Data [63] Continuation of Ser. No. 198,990, Nov.15, 1971, Pat. No. 3,790,560, which is a continuation-in-part of Ser.No. 158,075, June 29, 1971, abandoned, and a continuation-impart of Ser.No. 161,909, July 12, 1971, abandoned, which is a continuation-in-partof Ser. No. 156,100, June 23, 1971, abandoned.

[52] US. Cl 260/210 R; 260/9 R; 424/180 [51] Int. Cl. C07H 15/16 [58]Field of Search 260/210 R 1 *Oct. 28, 1975 [56] References Cited UNITEDSTATES PATENTS 3,790,560 2/1974 Bannister 260/210 R PrimaryExaminerJohnnie R. Brown Attorney, Agent, or Firm-Martin B. Barancik;Roman Saliwanchik 57 ABSTRACT 65 Claims, No Drawings DERIVATIVES OFLINCOMYCIN AND ITS ANALOGS AND PROCESS CROSS REFERENCE TO RELATEDAPPLICATIONS This application is a continuation of copending applicationSer. No. 198,990, filed Nov. 15, 1971, now U.S. Pat. No. 3,790,560,which is a continuation-in-part of application Ser. No. 158,075, filedJune 29, 1971 and now abandoned, and of application Ser. No. 161,909,filed July 12, 1971 and now abandoned, which is a continuation-in-partof application Ser. No. 156,100, filed June 23, 1971 and now abandoned.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to alkyl7-deoxy-7-RS -athiolincoseminides of Formula I and acylates thereof andto a process for making the same wherein n is l to 4, Alk is alkyl ofnot more than 4 carbon atoms, to wit, methyl, ethyl, propyl, isopropyl,butyl, sec.butyl, isobutyl, and tert.butyl, or 2- hydroxyethyl; R is aradical R,--XR wherein R is a saturated aliphatic hydrocarbon radical ofnot more than 18 carbon atoms, an unsaturated aliphatic hydrocarbonradical of not more than carbon atoms, an

aromatic hydrocarbon radical of not more than 1 1 carbon atoms, or anoxacarbocyclic aromatic or thiacarbocyclic aromatic hydrocarbon radicalof not more than 8 carbon atoms; XR; is hydrogen or 1 or 2 substituentswherein X is oxygen or sulfur and R is hydrogen, loweralkyl,loweralkenyl, lowercycloalkenyl, lowercycloalkenyl, loweralkoxyalkyl,loweralkylthioalkyl, phenyl, benzyl, furyl, furfuryl, thienyl, orthenyl; and wherein R, and R when alkyl, can be linked together to forman oxacycloalkyl of not more than 5 carbon atoms, having from 3 to 6ring members in the ring.

The compounds of Formula I can be obtained by heating in the presence ofglacial acetic acid or other anhydrous loweralkanoic acid, or anhydrousbenzoic acid or other arenoic acid of not more than 12 carbon atoms, analkyl N-acyl-6,7-aziridino-6-deamino-7- deoxy-a-thiolincosaminide of theformula:

wherein Ac and Ac, are carboxacyl and Alk is as given above, withsulfide of the formula R XR S,,R-

-YR, wherein n is 1, 2, 3, or 4; R and R are the same or different andare saturated aliphatic hydrocarbon radicals of not more than 18 carbonatoms, unsaturated aliphatic hydrocarbon radicals of not more than 10carbon atoms, cycloaliphatic hydrocarbon radicals of not more than 10carbon atoms, aromatic hydrocarbon radicals of not more than 1 1 carbonatoms; or oxacarbocyclic aromatic or thiacarbocyclic aromatichydrocarbon radicals of not more than 8 carbon atoms; R X and YR, arehydrogen or together not more than three substituents wherein X and Yare the same or different and are oxygen or sulfur and R and R are thesame or different and are hydrogen, carboxacyl (Ac loweralkyl,loweralkenyl, lowercycloalkyl, lowercycloalkenyl, loweralkoxyalkyl,loweralkylthioalkyl, phenyl, benzyl, furyl, furfuryl, thienyl, orthenyl; and wherein R and R when X is oxygen and R is alkyl, can belinked together to form an oxacycloalkyl of not more than 5 carbon atomsand having from three to 6 members. When it is desired that n be greaterthan 1 in the final product (Formula I), R -YR should be a radical thatreadily forms a carbonium ion, for example, tertiary butyl or allyl.Opening of the aziridine ring is thus effected yielding an acylatedalkyl 7-deoxy-7- 'RS -a-thiolincosaminide of the following formula:

wherein n, Ac, Ac X, R R and Alk are as given above.

The acyl groups are then removed by hydrazinolysis in a manner alreadywell known in the art (See U.S. Pat. No. 3,179,565) to yield alkyl7-deoxy-7-RS,,-athiolincosaminide of Formula I.

The compounds of the invention (Formula I) are useful for the samepurposes as methyl a-thiolincosaminide (methyl6-amino-6,8-dideoxy-l-thio-D-erythro-a- D-galacto-octopyranoside, a-MTL)as disclosed in U.S. Pat. No. 3,380,992 and as methyl 6-amino-7-chloro-6,7,8-trideoxy-l-thio-L-threoand D-erythro-a-D- galacto-octopyranosides(U.S. Pat. Nos. 3,496,163 and 3,502,648) and moreover can be acylatedwith trans-1- methyl-4-propyl-L-2-pyrrolidine carboxylic acid to formcarboxylic acids as disclosed in these patents or with anN-(2-hydroxyethyl)-L-2-pyrrolidine carboxylic acid to form compounds ofthe formula:

RS V

AcNH- where R, n, and Alk are as given and Ac isL-2-pyrrolidinecarboxacyl or an N-methyl, N-ethyl, or N-(2-hydroxyethyl)-L-2-pyrrolidinecarboxyacyl any or all of which can besubstituted in the 4-position with loweralkyl or loweralkylidene.

PRIOR ART It is known that 7-SH analogs can be prepared by heating anaziridino compound of Formula II where Ac and Ac are hydrogen withhydrogen sulfide (U.S. Pat. No. 3,544,551). It has not been possible,heretofore, to replace the S-hydrogen, either directly or indirectly.Moreover, the compounds of the invention are substantially more activethan the corresponding 7-SH compounds. For example,7-deoxy-7(S)-(methylthio)- lincomycin hydrochloride is several timesmore active in vitro against Gram positive bacteria than lincomycinwhereas 7-deoxy-7(S)-mercaptolincomycin hydrochloride is less activethan lincomycin.

It is also known that 7-OR analogs can be prepared by reacting acompound of Formula II with an alcohol in the presence of an acid.Efforts to produce the sulfur analogs by substituting the alcohol by amercaptan have been unsuccessful.

DETAILED DESCRIPTION It has now been found that compounds of Formula IIundergo sulfidolysis when heated with a sulfide (mono, di, tri, ortetra) in glacial acetic acid or other anhydrous lower-alkanoic acid oranhydrous benzoic acid or other arenoic acid of not more than 12 carbonatoms. The reaction appears to take the following course:

With a mixed sulfide the reaction may be considered as proceeding alongthese lines SMe /CH3 AcNH +CH Acoe isoPrOAc With a polysulfide thereaction follows this course 9 OAc CH3 CH CH n-i AcN E1 8 -SEt SEt HOAce With a mixed polysulfide an additional compound, namely, a disulfide,may be obtained, for example The formation of the polysulfide takesplace when R and/or R is a radical which readily forms a carbonium ion,for example, tert.butyl or allyl. In case of tert.butyl, the carboniumion could lose a proton to form isobutylene.

With any of the sulfides described above, the desired result is obtainedsimply by heating an alkyl N-acetyl-6,7-aziridino-6-deamino-7-deoxy-a-thiolincosaminide with the appropriatesulfide in glacial acetic acid or other anhydrous lower alkanoic acid oranhydrous benzoic acid or other arenoic acid of not more than 12 carbonatoms, for example, propionic or butyric acids.

Advantageously, a solvent toiling at about to 1 10 is used. Ordinarilyan excess of sulfide is used for this purpose. Such solvents as dioxane,carbon tetrachloride, benzene, or toluene can be used if desired andadvantageously with sulfides boiling above about The proportions are notcritical to the reaction, but are critical to the yields. Thus optimumyields are obtained with about 3 to 7 equivalents of acid coupled with asubstantial excess, at least twofold, of the sulfide. That is anotheradvantage of using the sulfide as a solvent. When a sulfide, such asmethyl sulfide which is so low boiling as to give a reaction mixturethat refluxes below 70", is used, super atmospheric pressure can beused; if it is such that the reaction mixture boils above about 110controlled heating can be used. Otherwise it is suitable to heat at thereflux temperature.

The reaction mixture can be worked up by procedures already well knownin the art such as countercurrent distribution, chromatography, andsolvent extraction or crystallization.

The starting compounds of Formula II exist in two epimeric forms asfollows:

AC V

SAI kyl OAc 6(R),7(R)- form OAC SAl kyl OAc;

6(R),7(S)- form by acylating a compound of the formula HH/ CH3 with acarboxacyl acylating agent, such as, acetic anhydride or other loweralkanoic acid anhydride or benzoyl chloride or like carboxacyl halide,in a manner al ready known in the art. Since the amino and hydroxygroups acylate at different rates the N-acyl, Ac, and the O-acyls, Accan be the same or different.

Inasmuch as these acyl groups (Ac and Ac,) do not appear in the finalproduct but are removed in the processing, it is immaterial what theyare as long as they are carboxyacyl. Suitable such carboxacyls arehydrocarboncarboxacyl containing not morethan 18 carbon atoms or halo-,nitro-, hydroxy, amino-, cyanothiocyano-, or alkoxysubstitutedhydrocarbon carbox acyls of not more than 18 carbon atoms, Advantageously, they are inert carboxacyls, that is to say, carboxacyls thatare not effected by the reaction. Most commonly they will be acetyl orother lower alkanoyl, or benzoyl or other aroyl of not more than 12carbon atoms. Nonetheless, they may be any carboxacyl.

The starting compounds of Formula VI can be prepared by thedehydrohalogenation of compounds of the formula:

1 Halo SAlkyl VII example, methanol. See Belgian Pat. No, 732,352, Oct.

The starting sulfides of formula R XR,-S,,--R- -YR are known compounds.R in Formula I is the radical R XR as defined above.

Suitable such starting sulfides (mono and poly) include for example,saturated aliphatic hydrocarbon sulfides, alkyl sulfides, which may besymmetrical or un symmetrical, where alkyl is methyl, ethyl, propyl,butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl,tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyland the isomeric forms thereof, for example, methyl sulfide, ethylmethylsulfide, ethyl sulfide, butyl sulfide, 2-butyl sulfide, tert.butylsulfide, methyl propyl sulfide, isopropyl methyl sulfide, ethyl propylsulfide, ethyl isopropyl sulfide, butylmethyl sul' fide, Z-butylmethylsulfide, isobutyl methyl sulfide, tert.butyl methyl sulfide; methylpentyl sulfide, isopropyl propyl sulfide, l-ethylpropyl methyl sulfide,ethyl isobutyl sulfide, tert.butyl ethyl sulfide, sec.butyl ethylsulfide, butyl ethyl sulfide, propyl sulfide, isopropyl sulfide, hexilmethyl sulfide, ethyl pentyl sulfide, isobutyl propyl sulfide, sec.butylpropyl sulfide, butyl propyl sulfide, isobutyl isopropyl sulfide,secbutyl isopropyl sulfide, tert.butyl isopropyl sulfide, butylisopropyl sulfide, pentyl propyl sulfide, heptyl methyl sulfide, ethyllmethylpentyl sulfide, ethyl hexyl sulfide, ethyl lethylbutyl sulfide,ethyl 1,3-dimethylbutyl sulfide, butyl isobutyl sulfide, butyl sec.butyl sulfide, isobutyl sulfide, methyl octyl sulfide, hexyl propylsulfide, butyl pentyl sulfide, butyl isopentyl sulfide, isopentylsulfide, pentyl sulfide, isopropyl octyl sulfide, isopropyl 1-methylheptyl sulfide, decyl methyl sulfide, nonyl propyl sulfide, butyll-propylpentyl sulfide, butyl octyl sulfide, butyl l-methylheptylsulfide, bis(l,3-dimethylbutyl)- sulfide, isohexyl sulfide, hexylsulfide, dodecyl methyl sulfide, propyl undecyl sulfide, nonyl pentylsulfide,

tolylthio)anisole, p-(p-to|ylthio)-anisole, p-(p-tolyldithio )-anisole,p-[ (2,Z-dimethylpropyl)thiol-anisole, 3-butylthio)-phenetole,1,2-dimethoxy-4-(phenylthio)- benzene,2,4-dimethoxy-1(phenylthio)-benzene, benzyloxy-(phenylthio)-methane,2-[(2- methoxyethyl)thio]-1,2,3 ,4-tetrahydronaphthylene, benzylp-(methylthio)phenyl ether, B-(ethylthio)-2-isopropyl-4-methyl-phenetole, 3-methyl- 4(propylthi0)-benzy1 propylether,- phenyl 2- (phenylthio)-vinyl ether,2(benzylthio)-tetrahydropyran, 3-[ (m-tolylthio )methyl]-3-oxetanemethanol, 3-[(o-tolylthio)methyl]-3-oxetanemethanol,3-[(ptolylthio)methyl]-3-oxetanemethanol, 1(epoxyethyl)-4-(phenylthio)-benzene, 2,5-bis(ethylthio)-furan, 2-[1-[2-(butylthio)-ethoxy]propyl]-furan, 2-[1-[2-(butylthio)ethoxy]butyl]-furan, 2-[l-[2-(butylthio)-ethoxy]buty1]-furan, 2-[l-[2-(butylthio)ethoxy]pentyl]-furan,2,3-bis(ethylthio)methyl]-thiophene, 3,4-bis[(ethylthio)methyll-thiophene, 2,5-bis[(propylthio )methyl]-furan,2-[ [2-(butylthio)ethoxy]methyl furan, 2,5-bis(butylthio)-thiophene,2,5-bis(tert.- butylthio)-thiophene,

2( tert.butylthio)-5-( hexylthio)-thiophene, 2-(tert.buty1thio)-5-(isopentylthio)-thiophene, 3 ,4bis(cyclohexylthio)-thiophene, 2,5-bis(phenylthio)- thiophene,2,5-bis(1-naphthylthio)-thiophene, 2-

(methylthio)-3-thiophenethiol, 5-(methylthio)-2-thiophenethiol,3(methyl-thio)-4-thiophenethiol, 3- (methylthio)-5-thiophenethiol,5-heptylthio-2- thiophenemethanol, 2-tert.butoxy-5-methylthiothiophene,2-(tert.butylthio)-5-(hexylthio)-thiopene,2-(diethoxymethyl)-5-ethyl-3-(ethylthio)-thiophene,3-(diethoxymethyl)-5-ethyl-2-(ethylthio)-thiophene, 2-(benzylthio)-3-(diethoxymethyl)-5-ethyl-thiophene, 2,5-bis(2-thienylthio)-thiophene,2,5-bis(3-thienylthio)-thiophene, 3,4-bis(2-thienylthio)-thiophene, 3,4-bis(3-thienylthio)-thiophene, 3,4-bis(cyclohexylthio)-2,5-bis(ethylthio)-thiophene.

Any of the above sulfides that contain one or more hyroxy or sulfhydrylgroups can be esterified. Usually these esters will be the acetate orthe benzoate but for reasons given above in respect to the Ac and Ac,groups, they can be any carboxacyl. In other words any of the hydrogensof these hydroxy or sulfhydryl groups can be replaced by an Ac groupwhich may be the same or different from the Ac groups in the 2-, 3-,4-0- positions.

By acylating the compounds of the invention (Formula I) with anL-2pyrrolidinecarboxylic acid, compounds of Formula IV in which Ac isthe acyl of the L-2-pyrrolidinecarboxylic acid are obtained. When Alkand R are methyl and the L-2-pyrrolidinecarboxy1ic acid istrans-1-methyl-4-propyl-L-2- pyrrolidinecarboxylic acid and theconfiguration is (S), the compound is 7-deoxy-7(S)-(methylthi0)-lincomycin which has antibacterial activity several times that oflincomycin. It and its analogs can be utilized for the same purposes andin the same way as lincomycin.

The compounds of the invention (Formula 1 as well as the acylatesthereof with an L-2- pyrrolidinecarboxylic acid can exist in either thefree base form or in the form of an acid addition salt. Unless otherwisespecified or otherwise dictated by the context both the acid additionform and the free base form are intended. These acid addition salts canbe made by neutralizing the free base with the appropriate acid to belowabout pH 7.0, and advantageously to about pH 2 to pH 6. Suitable acidsfor this purpose include hydrochloric, sulfuric phosphoric, thiocyanic,fluosilicic, hexafluoroarsenic, hexafluorophosphoric, acetic, succinic,citric, lactic, maleic, fumaric, pamoic, cholic, palmitic, mucic,camphoric, glutaric, glycolic, phthalic, tartaric, lauric, stearic,salicylic, 3-phenylsa1icylic, 5- phenylsalicylic, 3-methylglutaric,orthosulfobenzoic, cyclohexanesulfamic, cyclopentanepropionic, 1,2-cyclohexanedicarboxylic, 4-cyclohexenecarboxylic, octadecenylsuccinic,octenylsuccinic, methanesulfonic, benzenesulfonic, helianthic,Reineckes, dimethyldithiocarbmic, hexadecylsulfamic, octadecylsulfamic,sorbic, monochloroacetic, undecylenic, 4'-hydroxyazobenzene-4- sulfonic,octyldecylsulfuric, picric, benzoic, cinnamic, and like acids.

The acid addition salts can be used for the same purposes as the freebase or they can be employed to upgrade the same. For example, the freebase can be converted to an insoluble salt, such as the picrate, whichcan be subjected to purification procedures, for example, solventextractions and washings, chromatography, fractional liquid-liquidextractions, and crystallization and then used to regenerate the freebase form by treatment with alkali or to make a different salt bymetathesis. Or the free base can be converted to a watersoluble salt,such as the hydrochloride or sulfate and the aqueous solution of thesalt extracted with various water-immiscible solvents beforeregenerating the free base form by treatment of the thusextracted acidsolution or converted to another salt by methathesis.

The free bases can be used as buffers or as antacids. They react withisocyanates to form urethanes and can be used to modify polyurethaneresins. The thiocyanic acid addition salt when condensed withformaldehyde forms resinous materials useful as pickling inhibitorsaccording to U.S. Pat. Nos. 2,425,320 and 2,606,155. The free bases alsomake good vehicles for toxic acids. For example, the fluosilicic acidaddition salts are useful as mothproofing agents accordinf to U.S. Pat.Nos. 1,915,334 and 2,075,359 and the hexafluoroarsenic acid andhexafluorophosphoric acid addition salts are useful as parasiticidesaccording to U.S. Pat. Nos. 3,122,536 and 3,122,552.

The invention may now be more fully understood by reference to thefollowing examples in which the parts are by weight except where solventratios are given or except as otherwise specified and the c.g.s. systemis used unless otherwise specified.

EXAMPLE 1 7-Deoxy-7(S)-(methy1thio)-lincomycin Hydrochloride Part A-l:Methyl N-acetyl-2,3,4-tri-O-acety1-7-deoxy-7(S)-(methylthio)-a-thiolincosaminide A mixture of 5.0 gms. (1mol. equiv.) methyl N- acetyl-2,3,4-tri--acetyl-6(R),7(R)-aziridino-6-deamino-7deoxy-a-thiolincosaminide, 50 ccs. methyl sulfide, and 5.25gms. (7 mol. equivs.) glacial acetic acid is heated in a Pyrex sealedtube for hours in a steam-bath. Volatile materials are removed from theslightly pink reaction solution by distillation at 100 C., the residueis dissolved in methylene chloride and stirred with an excess ofsaturated aqueous sodium bicarbonate. Washing of the organic layer withwater, drying over anhydrous sodium sulfate, and removal of the solventon a rotating evaporator at 40/7 mm. gives a slightly pink solid (5.92gms.), showing no starting material by TLC (SiO gel, 1 acetone:1Skellysolve B) and a major new zone of slightly lower Rf. TLC refers tothin layer chromatography and Skellysolve B is technical hexane.

Countercurrent distribution of this solid in the system 1ethanol;1water;1 ethyl acetatez2 cyclohexane gives methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S (methylthio )-a-thiolincosaminide at a Kvalue of 1.21, as colorless rods from ethyl acetate-Skellysolve B havingthe following characteristics:

m.p. 225-226 C.

[01],, +225 (c, 0.9876, CHCl Analysis:

calcd. for c gHggogNszi C, 47.88; H, 6.47; N, 3.10; S, 14.20; M. Wt.451.55. Found: C, 47.87; H, 6.49; N, 3.19; S, 14.31; M. Wt. (Mass spec.,M") 451.

A mixture of 8.05 gms. methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S)-methylthio-a-thiolincosaminide (Part A-l) and 100ccs. hydrazine hydrate is stirred magnetically and heated under gentlereflux in an oil bath at 160 C. for 22 hrs. Removal of the volatilematerial from the colorless solution by distillation from the oil bathat 110 C./7 mm. gives methyl 7-deoxy- 7(S)-methylthio-a-thiolincosamide(B-l) as a colorless solid which crystallizes from methanol in colorlessneedles having the following characteristics:

m.p. 174175 C. [01],, +260 (0, 0.6790, H O) Analysis: I

Calcd. for C H O NS A C, 42.38; H, 7.47; N, 4.94; S, 22.63;

M. Wt. 283.41.

Found: C, 42.39; H, 7.52; N, 4.65; S, 22.78; M. Wt. (Mass spec., M")283.

Part C-l: 7-Deoxy-7(S)-(methylthio)-lincomycin hydrochloride [Methyl6,7,8-trideoxy-7-(methylthio)-6 trans-( l-methyl-4-propyl-L-2-pyrrolidinecarboxamido l -thio-L-threo-a-D-galactooctopyranosidehydrochloride] To a suspension of 4.15 gms. (2 mol. equivalents)transpropylhygric acid hydrochloride in 150 ccs. anhydrous acetonitrileis added 4.44 gms. (4.4 mol. equivs.) triethylamine. After the soliddissolves, the solution is cooled to 5 C. in an ice-methanol bath,causing the separation of triethylammonium chloride. To this solution isadded 2.73 gms. (2 mol. equivs.) of isobutyl chloroformate so that thetemperature does not exceed -3 C., and the reaction mixture stirred at 3to -5 C. for 20 minutes. Then 2.83 gms. (1 mol. equiv.) of methyl7-deoxy-7(S)-methylthio-a-thiolincosaminide (B-l in 20 ccs. methanol and20 ccs. water is added to the mixed anhydride, the precipitate oftriethylammonium chloride dissolving at once. After 2 hrs. TLC (SiO,gel, 1 MeOHzlO CHCL shows the disappearance of aminosugar, and thegeneration of a new zone of higher Rf. Volatile solvent is removed on arotating evaporator at 40/7 mm., and the syrupy residue dissolved inwater by the addition of dilute aqueous hydrochloric acid (N) till theresultant solution is at ca. pH 2. This acid solution is extracted twicewith methylene chloride, and the organic extracts discarded. The aqueoussolution is adjusted to pH 11 by the addition of aqueous sodiumhydroxide 50%), the resulting milky reaction mixture extractedthreetimes with methylene chloride, and the combinedextracts dried overanhydrous sodium sulfate, the residual alkaline aqueous layer beingdiscarded.

Removal of solvent from the methylene chloride extract on a rotatingevaporator at 40 C/7 mm. gives a slightly yellow syrup which ischromatographed on silica (1200 gms., columun dimensions 5.8 X cms.,hold-up volume 2000 ccs.) in the system 1 methanol: 1 5 chloroform.After a forerun of 1800 ccs. 50 cc. fractions are collected, and theelution of material followed by TLC on silica in the same system.

Fractions nos. 21-54, inclusive, are combined to yield, on removal ofsolvent, a colorless syrup which is converted to the hydrochloride bydissolving in water to which dilute aqueous hydrochloric acid (N) isadded till the solution is at ca. pH 3. This solution is thenshellfrozen and lyophilized yielding 7-deoxy7(S)-(methylthio)-lincomycin hydrochloride (C-3) as a colorless solid havingthe following characteristics:

Analysis:

Calcd. for C H O N S -HCI: C, 48.23; H, 7.88;-acetoxycyclohexylthio)-5.92; S,

M. Wt. 473.10 (M. Wt. free base, 436.63). Found: C, 48.84; H, 7.71; N,5.90) S, 12.96; Cl, 7.25; M. Wt. (Mass spec., M of free base) 436.Biological Activity: In vitro; about 8 times lincomycin, with improvedGram negative activity.

EXAMPLE 2 7-Deoxy-7(S )-(ethylthio)-lincomycin Hydrochloride Part A-2:Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(ethylthio)-a-thiolincosaminide Following the procedure ofPart A-l but substituting the methyl sulfide by ethyl sulfide andheating under reflux for 7 hours, there is obtained methyl N-acetyl-2,3,4-tri-0-acetyl-7deoxy-7(S)-(ethylthio)-athiolincosaminide (A-2)having the following characteristics:

K 1.85 (same solvent system) m.p. 236-237 C.

[011 +215 (c, 0.95, CHCI Analysis:

Calcd. for C H O NS C, 49.01; H, 6.71; N, 3.01; S, 13.77. Found: C,49.18; H, 6.47; N, 3.41; S, 13.17.

This compound is also obtained at a K value of 6.15 in thecountercurrent distribution of Example 12.

Part B-2: Methyl 7-deoxy-7(S)-(ethylthio)-athiolincosaminide Followingthe procedure of Part B-l the above compound (A-2) is converted tomethyl 7-deoxy-7(S)-(ethylthio)-athiolincosaminide (B-2). ltcrystallizes from methanol as colorless prisms having the followingcharacteristics:

m.p. l92-4 C.

[04] +253 (c, 0.73, H O) Analysis:

C, 44.42; H, 7.79; N,.4.71; S, 21.56. Found: C, 44.16; H, 7.78; N, 4.72;S, 21.78.

Part C-2: 7-Deoxy-7(S)-(ethylthio )-lincomycin hydrochloride Followingthe procedure of Part C-l the above compound (B-2) is converted to7-deoxy-7(S)-(ethylthio)- lincomycin hydrochloride (C-2). It is obtainedas a lyophilized colorless solid having the following properties:

[11],, +111 (c, 0,83, H O) Analysis:

Calcd. for C H o N s -Hcl:

C, 49.31; H, 8.07; N, 5.75; C], 7.28; S, 13.17;

M. Wt. 450.65 for free base.

Found (Corrected for 9.23% H O):

C, 49.52; H, 7.99; N, 5.61; Cl, 7.55; S, 13.46;

M. Wt. (Mass spec., M of free base) 450.

Biological activity: about 8 times lincomycin.

EXAMPLE 3 Alternative Process to Example 2 Following the procedure ofPart A-l substituting the ethyl sulfide by ethyl disulfide and heatingin an oil bath at 110 for 20 hours, the same 7(S)-(ethylthio) compoundis obtained but in higher yields.

EXAMPLE 4 7-Deoxy-7(S)-(propylthio) lincomycin Hydrochloride Part A-4:Methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S)-(pr0py1thio)-a-thiolincosaminide Following the procedure ofPart A-l substituting the methyl sulfide by methyl propyl sulfide,methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S)-(propylthio)-athiolincosaminide(A-4) is obtained from ethyl acetatezSkellysolve B as colorless needleshaving the following characteristics:

[a],, +203 (c, 0.96, CHCL Analysis:

Calcd. for C H O NS C, 50.08; H, 6.93; N, 2.92; S, 13.37. Found: C,49.89; H, 6.96; N, 3.02; S, 13.41.

K 3.10 (Same solvent system) There is also obtained the corresponding7(S)- methylthio)- compound (A-1) at a K value of 1.32, in the ratio ofone part to three parts of the 7(S)- (propylthio)- compound (A-4).

Part B-4: Methyl 7-deoxy-7(S)-(propylthio)-athiolincosaminide Followingthe procedure of Part B-l, the compound (A4) is converted to methyl7-deoxy-7(S)- (propylthio)-a-thiolincosaminide (B-4). It crystallizesfrom methanol as colorless platelets having the followingcharacteristics:

[01],, +257 (c, 0.,71, pyridine) Analysis:

Calcd. for C H O NS C, 46.27; H, 8.09; N, 4.50; S, 20.59. Found: C,46.30; H, 8.21; N, 4.38; S, 20.58.

Part C-4: 7-Deoxy-7(S)-(prOpylthio)-lincomycin hydrochloride Followingthe procedure of Part C-l the above compound (B-4) is converted to7-deoxy-7(S)- (propylthio)-lincomycin hydrochloride (C-4) as a1yophilized colorless amorphous solid having the followingcharacteristics:

[c11 +1 12 (c, 0.83, H O) Analysis:

C, 50.33; H, 8.25; N, 5.59; C], 7.08; S, 12.80;

M. Wt. free base 464.68.

Found (Corrected for 5.33% H O): C, 50.12; H, 8.03; N, 5.74; Cl, 6.94:S, 12.57; M. Wt. (Mass spec., M of free base) 464.

Biological Activity: about 8 times lincomycin.

EXAMPLE 5 Alternative for Example 4 Following the procedure of Part A-2,substituting the ethyl sulfide by propyl sulfide, there is obtainedmethyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(propylthio)-a-thiolincosaminide (A14).

EXAMPLE 6 7-Deoxy-7(,S)-(isopropylthio)-lincomycin Hydrochloride PartA-6: Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7-(S)-(isopropy1thio)-a-thiolincosaminide Following the procedureof Part A-2 substituting the ethyl sulfide by methyl isopropyl sulfide,there is obtained methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(isopropylthio)-a-thiolincosaminide from ethyl acetate (A-6). Itcrystallizes as colorless needles having the following characteristics:

K 2.94 in the system 1 ethanolzl water:1 ethyl acetate: 2 cyclohexanem.p. 274.5 -275.5 C.

[04] +200 (c, 0.87, CHCl Analysis:

Calcd. for C oH33OgNS2:

C, 50.08; H, 6.93; N, 2.92; S, 13.37. Found: C, 49.79; H, 6.95; N, 2.78;S, 13.60.

Also formed is the 7(S)-methylthio compound (K 1.32) in the ratio of 1.5methylthio to l isopropylthio.

Substituting the methyl isopropyl sulfide by isopropyl disulfide thereis obtained exclusively methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(isopropylthio)-athiolincosaminide.

Part B-6: Methyl 7-deoxy-7(S)-(isopropylthio)-athiolincosaminideFollowing the procedure of Part-B-l, the above isopropylthio compound(A-6) is converted to methyl 7- deoxy-7(S)-(isopropy1thio)-a-thiolincosaminide as colorless platelets frommethanol having the following characteristics:

m.p. 220 221 C.

[a] 269 (c, 0.85, pyridine) Analysis:

Calcd. for C, H O.,NS

C, 46.27; H, 8.09; N, 4.50; S, 20.59. Found: C, 46.02; H, 8.10; N, 4.45;S, 20.73.

Part C-6: 7-Deoxy-7(S)-(isopropylthio)-lincomycin hydrochlorideFollowing the procedure of Example 1, Part C-l, there is obtained7-deoxy-7(S)-(isopropylthio)- lincomycin hydrochloride having thefollowing characteristics: [11],, +109 (c, 0.97, H O) Analysis:

C, 50.33; H, 8.25; N, 5.59; Cl, 7.08; S, 12.80;

M. Wt. free base 464.68.

Found (Corrected for 5.00% H O):

C, 50.74; H, 8.50; N, 5.36; CI, 6.74; S, 12.67; M. Wt.

(Mass spec., M* of free base) 464.

EXAMPLE 7 7 S )-(CycloHexylthio )-7-deoxylincomycin Hydrochloride PartA-7: Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclohexylthio)-a-thiolincosaminide Following the procedureof Example 1, Part A-l, substituting the methyl sulfide by cyclohexylmethyl sulfide but heating in an oil bath at 115 for 24 hours, there isobtained methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclohexylthio)-a-thiolincosaminide (K 5.95 using the system1 ethanolzl waterzl ethyl acetate: cyclohexane) as colorless prisms fromethyl acetate having the following characteristics:

m.p. 248-250 C. [01],, +184 (c, 0.86, CHCl Analysis:

Calcd. for C H ,O,,NS

C, 53.15; H, 7.18; N, 2.70; S, 12.34. Found: C, 53.27; H, 7.28; N, 2.79;S, 11.92.

There is also obtained corresponding 7(S)-(methylthio)-compound (K 0.57)and otherwise characterized as the compound of Part A-l in a ratio ofabout 1 part to each 5 parts of the (7(S)-cyclohexylthio compound.

Part 13-7: Methyl 7-deoxy-7(S)-(cyclohexylthio)-athiolincosaminideFollowing the procedure of Example 1, Part B-l, there is obtainedvmethyl 7-deoxy-7(S)- (cyclohexylthio)-a-thiolincosaminide as colorlessneedles from methanol having the following characteristics:

m.p. 222 223 C.

[01] +235 (c, 0.62, pyridine) Analysis:

Calcd. for :C, H O,NS

c, 51.25; H, 8.32; N, 3.99; 5, 18.24. Found: C, 50.94; H, 8.46; N, 3.69;S, 18.47.

Part C-7: 7(S)-(CycloHexylthio)-7-deoxylincomycin hydrochlorideFollowing the procedure of Example 1, Part C-l, there is obtained7(S)-(cyclohexylthio)-7-deoxylincomycin hydrochloride having thefollowing characteristics:

[01],, (c, 0.54, H O) Analysis:

C, 53.26; H, 8.38; N, 5.18; S, 11.85; C], 6.55;

M. Wt. free base 504.74. Found (Corrected for 4.42% H O):

C, 53.50; H, 8.43; N, 5.16; S, 11.96; Cl, 6.33;

M. Wt. (Mass spec., M of free base) 504.

EXAMPLE 8 Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclopentylthio)-a-thiolincosaminide 1 Following the procedure ofExample 1, Part A-l, substituting the methyl sulfide by methylcyclopentyl sulfide but heating in an oil bath at C. for 16 hrs., thereis obtained methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclopentylthio)-a thiolincosaminide (A-8) at a K value of4.0 using 1 ethanolzl water:l ethyl acetate:3 cyclohexane. It isobtained as colorless needles from ethyl acetate having the followingcharacteristics:

[01],, +l87 (c, 0.99, chloroform) Analysis:

Calcd. for C22H3503NS2Z C, 52.25; H, 6.98; N, 2.77; S, 12.68.

Mol. Wt. 505.64. Found: C, 52.07; H, 6,88; N,2.68; S, 12.62. Mol. Wt.(Mass spec., M 505.

When methyl cyclopentyl sulfide is substituted by cyclopentyl disulfide,the same compound is obtained.

EXAMPLE 9 7(S)-(Butylthio)-7-deoxylincomycin hydrochloride Part A-9:Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(butylthio)-7-deoxty-a-thiolincosaminide Following the procedure ofExample 3, substituting the ethyl disulfide by butyl disulfide, there isobtained methyl N-acetyl-2,3,4-tri-O-acetyl 7(S)-(butylthio)-7-deoxy-a-thiolincosaminide (K 3.35, 1 ethanolzl water:] ethyl acetate:3cyclohexane) as colorless needles from ethyl acetate having thefollowing characteristics:

[04],; +197 (c, 0.51, CHCl Analysis:

Calcd. for C H O NS C, 51.09; H, 7.15; N, 2.84; S, 12.99.

Found: C, 51.05; H, 7.21; N, 2.63; S, 12.76.

Part B-9: Methyl 7(S)-(butylthio)-7-deoxy-athiolincosaminide Followingthe procedure of Example 1,'Part B-l, there is obtained methyl7(S)-(butylthio)-7-deoxy-athiolincosaminide as colorless plates frommethanol having the following properties:

m.p. 188190 C.

[041 +250 (c, 1.00, pyridine) Analysis:

Calcd. for C, H -,O.,NS

C, 47.97; H, 8.36; N, 4.30; S, 19.70. Found: C, 47.88; H, 8.33; N, 4.37;S, 19.69.

Part C-9: 7-Deoxy-7(S)-(butylthio)-lincomycin hydrochloride Followingthe procedure of Example 1, Part C-b 1, there is obtained7-deoxy-7(S)-(butylthio)-lincomycin hydrochloride having the followingcharacteristics:

[11],, +106 (c, 0.65, H O) Analysis:

Calcd. for C H O N S -HCl:

C, 51.29; H, 8.41; N, 5.44; S, 12.45; :Cl, 6.88;

M. Wt. of free bases 478.70.

Found (Corrected for 3.82% water):

C, 51.05; H, 8.70; N, 5.13; S, 12.28; Cl, 6.69; M. Wt. (Mass spec., M offree base) 478.

EXAMPLE l0 7-Deoxy-7(S)-(2-hydroxyethylthio)-lincomycin hydrochloridePart A-lOa: Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxyethylthio)-60 -thiolincosaminide Following theprocedure of Example 1, Part A-l, substituting the methyl sulfide by2-hydroxyethyl methyl sulfide but heating on a steam bath at 100 for 5hours, there is obtained methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-( 2-hydroxyethylthio)-athiolincosaminide (K =O.97, 1ethanolzl waterzl ethyl acetate:0.5 cyclohexane) as colorless needlesfrom ethyl acetate-Skellysolve B having the following properties:

m.p. 226-228 C.

[a],, +185 (c, 1.00, CHC1 Analysis:

Calcd. for C H O NS C, 47.38; H, 6.49; N, 2.91; S, 13.32.

Found: C, 47.18; H, 6.79; N, 2.86; S, 12.73.

Part A-lOb: Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-acetoxyethylthio )-a-thiolincosaminide Following theprocedure of Example 1, Part A-l, substituting the methyl sulfide by2-acetoxyethyl methyl sulfide but heating on a steam bath at 100 for 5hours, there is obtained methyl N-acetyl-2,3,4-tri-O-acety1-7-deoxy-7(S)-(2-acetoxyethylthio)-athiolincosaminide (K =0.53, 1ethanolzl waterzl ethyl acetate:3 cyclohexane) as colorless needles fromethyl acetate-Skellysolve B having the following properties:

[01],, +180 (c, 0.79, CHCl Analysis:

Calcd. for C H O NS C, 48.17; H, 6.35; N, 2.68; S, 12.25. Found: C,48.12; H, 6.37; N, 2.58; S, 11.95.

Part B-lO: Methyl 7(S)-(2-hydroxyethylthio)-7- deoxy-a-thiolincosaminideFollowing the procedure of Example 1, Part B-l there is obtained fromcompound A-lOa or A-lOb, 7-deoxy-7(S)-(Z-hydroxyethylthio)-a-thiolincosaminide as colorlessplatelets from acetonitrile-ethanol having the following properties:

m.p. 175 6C.

[a] +234 (c, 0.52, H O) Analysis:

Calcd. for CIH23O5NSZI C, 42.15; H, 7.40; N, 4.47; S, 20.46. Found: C,42.05; H, 7.55; N, 4.43; S, 20.36.

Part C-lO: 7-Deoxy-7(S)-(2-hydroxyethylthio)- lincomycin hydrochlorideFollowing the procedure of Example 1, Part C-l, there is obtained7-deoxy-7(S)-(2-hydroxyethylthio)- lincomycin hydrochloride as acolorless amorphous material by lyophilization from aqueous solutionhaving the following characteristics:

[01],, +114 (c, 0.9], H 0) Analysis:

C, 47.74; H, 7.81; N, 5.57; Cl, 7.05; 5, 12.75;

M. Wt. of free base 466.65. Found (Corrected for 6.75% H O):

C, 48.05; H, 7.70; N, 5.10; CI, 6.96; S, 12.50;

M. Wt. (Mass spec., M of free base) 466. This compound is about 8 timesas active as lincomycin and has greater Gram negative activity in vivo,and is less toxic, than 7-deoxy-7 (S)-chlorolincomycin hydrochloride.

EXAMPLE 1 l 7(S )-(tert.Butylthio)-7-deoxylincomycin hydrochloride PartA-l 1: Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(tert.butylthio)-7-deoxy-a thiolincosaminide Following the procedure ofExample 1, Part A-l, substituting the methyl sulfide by ter.butyl2-mercaptoethyl sulfide but heating in an oil bath at C. for 16 hrs.,there is obtained crude methyl N-acetyl---2,3,4-tri-O-acetyl-7(S)-(tert.butylthio)-7-deoxy-athiolincosaminide.

Countercurrent distribution in the system 1 ethanokl water:1 ethylacetate:3 cyclohexane yields methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(tert.butylthio)-7-deoxy-a-thiolincosaminide at a K value of 2.38. It is obtained as smallcolorless needles from ethyl acetate having the followingcharacteristics:

m.p. 272 3 C.

[01],, +187 (c, 0.64, chloroform) Analysis:

Calcd. for C H O NS C, 15.09; H, 7.15; N, 2.84; S, 12.99.

Mol. Wt. 493.63. Found: C, 51.19; H, 7.28; N, 2.95;

Mol. Wt. (Mass spec., M") 493.

The same compound is obtained but in lower yields when the methylsulfide of Part A-l is substituted by tert.butyl sulfide.

Part B-1 1: thiolincosaminide Following the procedure of Part B-l, thereis obtained methyl 7(S)-(tert.butylthio)-7-deoxy-athiolincosaminide.Part C-ll; 7(S)-(tert.Butyltl1io)-7- deoxylincomycin hydrochloride 7(S)-(tert.Butylthio )-7-deoxy-a- Following the procedure of Part C-l,there is obtained 7(S)-(tert.butylthio)-7-deoxylincomycin hydrochlorideas an amorphous solid obtained by lyophilizing an aqueous solution.

Part D-l 1: Methyl N-acetyl-2,3,4-triOacetyl-7(S)-[2-(tert.butylthi0)ethylthio]-7-deoxy-athiolincosaminide The abovecountercurrent distribution (Part A-ll) yields also methylN-acetyl-2,3,4-tri-O-acetyl-7(S)-[2-(tert.butylthio)ethylthio]-7-deoxy-a-thiolincosaminide at a K value of7.95. It is obtained as colorless, irregular platelets from ethylacetate-Skellysolve B having the following characteristics:

m.p. 164 C.

[01],, +164 (c, 0.58, chloroform) Analysis:

Calcd. for C H O NS C, 49.88; H, 7.10; N, 2.53; S, 17.37.

Mol. Wt. 553.75.

Found: C, 49.76; H, 7.03; N, 2.63; S, 17.39. Mol. Wt. (Mass spec., M*)553.

The tert.butyl Z-mercaptoethyl sulfide is obtained from the reactionbetween sodium tert.butyl mercaptide and ethylene sulfide in ethanolsolution.

Following the procedures of Parts B-1 and C-1 there are obtained methyl7(S)-[2-(tert.butylthio)ethylthio1- 7-deoxy-a-thiolincosaminide and7(S)-[2- (tert.butylthio)ethylthio]-7-deoxylincomycin hydrochloride.

EXAMPLE 12 Part A-l2: Methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy7(S)-(ethyldithio)-a-thiolincosaminide Following the procedure ofExample 1 substituting the methyl sulfide by tert.butyl ethyl disulfidebut heating in an oil bath at 100 C. for 16 hrs. there is obtained acrude product containing methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S)-(ethyldithio)-athiolincosaminide. Countercurrentdistribution of this crude material in the system 1 ethanolzl water:lethyl acetate:3 cyclohexane yields methyl 4 -acetyl-2,3,4-tri-0'acetyl-7-deoxy-7(S)-(ethyldithio)-athiolincosaminide (A-12) admixedwith methyl 4-acetyl-2,3,4-tri-Oacetyl-7(S)-(tert.butylthio)-7-deoxya-thiolincosaminide(A-l l) in the proportions of 30 to 70, respectively. The K value ofthis mixture is 2.57. The two products are separable by vapor-phasechromatography and are differentiated by the fact that the former (A-l2)shows a UV absorption at 245 nm, e, 546 whereas the latter (A-ll) showsno UV absorption. The former compound (A-l 2) shows a molecular ion' atm/e 497 by mass spec. as against a calculated value of 497.65. Thelatter compound (A-] 1) is identical with that obtained in Part A-l 1.Part 8-12:

A solution of 600 mg. of the mixture (A-ll and A-12) of Part A-l2 in 60ml. of benzene and 2.72 g. of trisdiethylaminophosphine is heated undergentle reflux for hrs. The solvent is removed by distillation underreduced pressure and the resulting syrup chromatographed on silica using1 ethyl acetatezl Skellysolve B as the solvent system in order toseparate excess reagent and coproduced trisdiethylaminophosphine sulfidefrom the product which appears at an Rf of 0.5 10.54. Countercurrentdistribution ofthis product in 1 ethanolzl waterzl ethyl acetate: 3cyclohexane yields methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S-)-ethylthio-a-thiolincosaminide (A-Z) at a K value of1.43 and tertbutyl analog (rt-1 i) at a K value 2.57.

Following the procedures of Parts B-1 and C-l. there are obtained fromthe above 30-70 mixture, 1) a corresponding mixture of methyl7-deoxy-7(S)- (ethyldithio)-a-thiolincosaminide and methyl 7(S)-(tertbutylthio)-7-deoxya-thiolincosaminde, and 2) a correspondingmixture of 7-deoxy7(S)-(ethyldithio)- lincomycin hydrochloride and7(S)-(tert.butylthio)- lincomycin hydrochloride.

EXAMPLE l3 7(S tert.Butyldithio)-7-deoxylincomycin hydrochloride PartA-l3: Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(tert.butyldithio)-7--deoxy-oz-thiolincosaminide Following the procedureof Example 3, substituting the ethyl disulfide by tert.butyl disulfide,there is obtained methyl N-acetyl-Z.3,4-tri-0-acetyl-7(S)-(tert.butyldithio )-7-deoxy-a-thiolincosaminide as small colorless rodsfrom ethyl acetatezSkellysolve B having the following characteristics:

m.p. 241-2 C.

[01] +220 (c, 0.56, CHCI (K 7.35, l waterzl ethanolzl ethyl acetate:3cyclo hexane) Analysis:

Calcd. for C H O NS C, 47.98; H, 6.71; N, 2.67; S, 18.30. Found: C,48.03; H, 6.65; N, 2.65; S, 18.65;

M. Wt. (Calcd.) 525.70.

Found (Mass spec., M) 525 This compound is also obtained at a K value of1.43 in the countercurrent distribution in Example 12.

EXAMPLE 14 Alternate for Example 1 Following the procedure of Example 3,substituting the ethyl disulfide by methyl tertiary butyl sulfide, thereis obtained methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy- 7(S)-(methylthio)-a-thiolincosaminide which is the same compound as obtainedin Example 1, Part A-l. The advantage of this alternative process isthat higher yields of the desired product are obtained.

EXAMPLE 15 Alternative for Example 1 Following the procedure of Example3, substituting the ethyl disulfide by l,2bis(methylthio)-ethane, thereis obtained methyl N-acetyl-2,3,4tri-O,-acetyl-7-deoxy-7(S)-(methylthio)-a-thiolincosaminide which is identical to the productobtained in Example 1, Part A-l. This process, also giving improvedyields, quite unexpectedly does not produce any of the 7(S)-[2-(methylthio)ethylthio]-compound.

EXAMPLE l6 7-Deoxy-7(S)-[(Z-methylthio)ethylthioHincomycin hydrochlorideand Alternative to Example 1 Part A-16:

Following the procedure of Example 3, substituting the ethyl disulfideby 2-(methylthio)ethanethiol, there is obtained methylN-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S)-(methylthio)-a-thiolincosaminide, which is the same compound asobtained in Example 1, together with methylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy7(S)-[(2-methylthio)-ethylthiolax-thiolincosaminide in the proportions of 80parts of the former and 20 parts of the latter. Counter-currentdistribution in the system 1 ethanolzl waterzl ethylacetatez3cyclohexane yields the latter compound at a K value of 1.84. Itis obtained as colorless needles from ethyl acetate-Skellysolve B havingthe following characteristics:

[01] +l83 (c, 0.93, chloroform) Analysis:

Calcd. for C H O NS C, 46.94, H, 6.50; N, 2.74; S, 18.80;

Mol Wt. 511.67. Found: C, 46.96; H, 6.92; N, 2.49; S, 18.38; Mol. Wt.(Mass spec., M") 511.

Part B-16: Methyl 7-deoxy-7(S)-[(2-methylthi)ethylthio]-a-thiolincosaminide Following the procedure of Part8-] using the above compound (A-16) as the starting compound, there isobtained methyl 7-deoxy-7(S)-[(2- methylthio )ethylthio-a-thiolincosaminide.

Part C-16: 7-De0xy-7(S)-[(2-methylthio)ethylthio]- lincomycinhydrochloride Following the procedure-of Part C-l using the abovecompound (B-16) as starting compound, there is obtained7-deoxy-7(S)-[(Z-methylthio)ethylthio]lincomycin hydrochloride.

EXAMPLE 17 Alternative to EXAMPLE 1 Following the procedure of Example3, substituting the ethyl disulfide by 4-(methylthio)butanethiol, thereis obtained methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy7(S)-methylthio-a-thiolincosaminide which is identical with thecompound of Part A-l.

The 4-(methylthio)butanethiol is obtained by the mono-S-methylation ofthe 1,4-butanedithiol using one equivalent of sodium hydroxide andmethyl iodide in ethyl alcohol.

EXAMPLE 18 Alternative to Example 3 Following the procedure of Example3, substituting the ethyl disulfide by ethyl trisulfide but heating inan oil bath at 100 for 16 hrs., the same 7(S)-ethylthio compound isobtained in good yields.

EXAMPLE l9 7-Deoxy7(S)-[ 3-methylthio )propylthio1lincomycinhydrochloride Part A-19: Methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy7(S)-[(3-methylthio)propylthiol-athiolincosaminide Following theprocedure of Example 15, substituting the ethyl trisulfide by1,3-bis(methylthio)-propane, there is obtained methylN-acetyl-Z,3,4-tri-O-acetyl-7-deoxy-7(S)-[(3-methylthio)propylthio1-athiolincosaminide.

By countercurrent distribution using the same solvent system as inExample 16, the above compound is obtained at a K value of 2.24. Itcrystallizes from ethyl acetate as colorless needles having thefollowing characteristics:

m.p. 21112 C.

[01],, +18 1 (c, 1.1, chloroform) Analysis:

C, 47.93; H, 6.71; N, 2.67; S, 18.30;

Mol. Wt. 525.70.

Found: C, 47.97; H, 6.78; N, 2.62; S, 17.73; M01. Wt. (Mass spec., M525.

Following the procedures of Parts B-1 and C-1 using the above compound(A-19) as the starting compound, there are obtained methyl7-deoxy-7(S)-[(3- methylthio)propylthio]-a-thiolincosaminide and 7-deoxy-7(S)-[(3-methylthio)propylthiol]lincomycin hydrochloride. Thisprocess does not produce the methylthio derivative. The product isexclusively the 3-(methylthio)propylthio compound.

EXAMPLE 20 Part A-20:

Following the procedure of Example 16 substituting the2-(methylthio)ethanethiol by 2-(methylthio)ethanethiol acetate, there isobtained methyl N-acetyl-2,3,4-tri-0-acetyl-7(S)-(2-acetylthioethylthio)-7-deoxy-a-thiolincosaminide; countercurrent distribution using the samesolvent system as in Example 16, yields this compound at a K value of1.55. It is obtained as small colorless rods from ethyl acetate havingthe following characteristics:

m.p. 198-9 C.

[a],, +168 (c, 1.0. chloroform) Analysis:

Calcd. for C2 H33O9Ns I C, 46.73; H, 6.16; N, 2.60; S, 17.63;

Mol. Wt. 539.68.

Found: C, 46.84; H, 6.05; N, 2.56; S, 17.52; Mol. Wt. [(Mass spec., M-HCHS]493.

Following the procedures of Parts B-1 and C-1, using the above compound(A-20) as the starting compound, there are obtained methyl7-deoxy-7(S)-(2- mercaptoethylthio)-a-thiolincosaminide and 7-deoxy-7(S)-(Z-mercaptoethylthio)-lincomycin hydrochloride.

EXAMPLE 21 Part A-21:

Following the procedure of Example 1, Part A-l, substituting the methylsulfide by Z-methoxyethyl methyl sulfide and heating in an oil bath atfor 16 hours, there is obtained methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy7(S)-(2-methoxyethylthio)-athiolincosaminide.Countercurrent distribution using 1 ethanolzl waterzl ethyl acetate:2cyclohexane as the solvent system gave this compound at a K value of0.88. It is obtained as colorless rods from ethyl acetate having thefollowing characteristics:

m.p. 2257 C. [11],, +17l (c, 0.90, chloroform) Analysis:

Calcd. for CgoHaaOgNSg:

C, 48.47: H, 6.71; N, 2.83; S, 12.94;

Mol. Wt. 495.60.

Found: C, 48.72; H, 6.82; N, 2.79; S, 12.77; M01. Wt. (Mass spec., M*)495.

Part B-21: Methyl 7-deoxy-7(S)-( 2-methoxyethylthio)-a-thiolincosaminide Following the procedure of PartB1, there is obtained methyl7-deoxy-7(S)-(2-methoxyethylthio)-athiolincosaminide as colorlessneedles from acetonitrile having the following characteristics:

m.p. 169170 C.

[0:] +223 (c, 0.93, water) Analysis:

CalCd. for C12H2505NS2:

C, 44.01; H, 7.70; N, 4.28; S, 19.58;

Mol. Wt. 327.46. Found: C, 44.31; H, 7.53; N, 4.20; S, 19.42; Mol. Wt.(Mass spec., M 327.

Part C-21: 7-Deoxy-7(S)-(2-methoxyethylthio)lincomycin hydrochlorideFollowing the procedure of Part C-l, there is obtained7-deoxy-7(S)-(2-methoxyethylthio)lincomycin hydrochloride as alyophilized colorless amorphous solid having the followingcharacteristics:

[01],, +106 (c, 0.70, water) Analysis:

C, 48.77; H, 7.99; N, 5.42; CI, 6.86; S, 12.40;

Mo]. Wt. (of free base) 480.68. Found (Corrected for 4.94% water):

C, 48.90; H, 7.95; N,5.51; Cl. 6.60; S, 12.23; Mol. Wt. (Mass spec., Mof free base) 480.

EXAMPLE 22 Part A-22: Methyl N-acetyl-2,3,4-tri--acetyl-7-deoxy-7(S)-(vinylthio)-a-thiolincosaminide Following the procedure ofPart A-l substituting the methyl sulfide by methyl vinyl sulfide andthen heating at 100 for 16 hours, there is obtained methyl N-acetyl2,3,4-tri-0-acetyl-7-deoxy-7(S)-(vinylthio)-athiolincosaminide.Countercurrent distribution in the solvent system 1 ethanol:l waterzlethyl acetate:3 cyclohexane yields this compound at a K value of 1.57.It is obtained as colorless needles from ethyl acetate- Skellysolve Bhaving the following characteristics:

m.p. 2lS.5-216 C.

[a],, +l68 (c. 0.79, chloroform) Analysis:

Calcd. for C H O NS C, 49.23; H, 6.31; N, 3.02; S, 13.83;

Mo]. Wt. 463.56.

Found: C, 49.06; H, 6.39; N, 3.13; S, 13.33; Mol. Wt. (Mass spec., M*)463.

Following the procedures of Parts B -1 and C-1 using the above compound(A-22) as the starting compound, there are obtained methyl7-deoxy-7(S)-(vinylthio)-athiolincosaminide and7-deoxy-7(S)-(vinylthio)lincomycin hydrochloride.

EXAMPLE 23 Part A-23: Methyl N-acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S)-(allylthio)-a-thiolincosaminide and MethylN-acetyl-Z,3,4-tri-0-acetyl-7-deoxy-7(S)-(propenylthio)-a-thiolincosaminide Following the procedure of Part A-lsubstituting the methyl sulfide by allyl sulfide and heating at 100 for16 hours, there is obtained methyl N-acetyl-2,3,4-tri-0-acetyl7(S)-(allylthio)-7-deoxy-a-thiolincosaminide. There is alsoobtained methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy7(S)-(propenylthio)-athiolincosaminide. Countercurrentdistribution using the solvent system I ethanol:l waterzl ethylacetate:2 cyclohexane yields the allyl compound at a K value of 1.76 andthe propenyl compound at a K value of 3.30. The allyl compoundcrystallized from ethyl acetateS- kellysolve B as colorless needleshaving the following characteristics:

[01],, +194 (c, 0.63, chloroform) Analysis:

Calcd. for czoHg oaNsz:

C, 50.29; H, 6.54; N, 2.93; S, 13.43;

Mol. Wt. 477.59.

Found: C, 50.10; H, 6.67; N, 2.79; S, 13.00; Mol. Wt. (Mass spec., M+)477.

The propenyl compound is obtained as colorless needles from ethylacetate-Skellysolve B having the following characteristics:

m.p. 273-5 C.

[01],, +157 (c, 1.05, chloroform) Analysis:

Calcd. for C H O NS same as above Found: C, 50.43; H, 6.45; N, 2.96; S,13.37; Mol. Wt. (Mass spec., M 477.

Following the procedure of Parts B-1 and C-1 using the above compounds(A-23 allyl and A-23 propenyl) as the starting compounds, there areobtained methyl 7(S)-(a1lylthio)-7-deoxy-a;thiolincosaminide, methyl7-deoxy-7(S)-(propenylthio)-a-thiolincosaminide, 7(-S)-(allylthio)-7-deoxylincomycin hydrochloride, and7-deoxy-7(S)-(propenylthio)-lincomycin hydrochloride.

EXAMPLE 24 Part A-24: Methyl N-acetyl-2,3,,4-tri-O-acetyl-7(S)-(allyldithio)-7-deoxy-a-thiolincosaminide The procedure of Part A-l,substituting the methyl sulfide by allyl disulfide and heating at C. for16 hours is followed and the product chromatographed over silica gelusing 1 ethyl acetate:l Skellysolve B as the solvent system to removeexcess reagent (of low polarity) followed by straight ethyl acetate toremove the more polar desired products. Countercurrent distribution ofthe latter using 1 ethanolzl eaterzl ethyl acetate:3 cyclohexane as thesolvent system yields methylN-acetyl-2,3,4-tri-0-acetyl-7(S)-(allyldithio)-athiolincosaminide (A24)at a K value of 5.66. It crystallizes from ethyl acetate as stout,colorless prisms having the following characteristics:

[01],, +25l (c, 1.00, chloroform) Analysis:

Calcd. for C H O NS C, 47.13; H, 6.13; N, 2.75; S, 18.88;

Mol. Wt. 509.66.

Found: C, 47.03; H, 6.16; N, 2.56; S, 18.68; Mol. Wt. (Mass spec., M509.

The allylthio analog (A-21 allyl) is also obtained at a K value of 2.03.

Following the procedures of parts B-1 and C-1 there are obtained methyl7(S)-( allyldithio)-7-deoxy-athiolincosaminide and7(S)-(allyldithio)-7-deoxylincomycin hydrochloride.

EXAMPLE 25 Part A-25: Methyl N acetyl-2,3,4-tri-0-acetyl-7-deoxy-7(S)-(2,3-dihydroxypropylthio)-athiolincosaminide Following theprocedure of Part A- l, substituting the methyl sulfide by2,3-dihydroxypropyl methyl sulfide, there is obtained methylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2,3-dihydroxypropylthio)-athiolincosaminide. Countercurrentdistribution using 1 ethanol:1 water;1.5 ethyl acetate:0.5 cyclohexaneyielded this compound at a K value of 0.91. It is obtained as colorlessplatelets from ethyl acetate having the following characteristics:

m.p. 255-7 C. 11; 6 (c. .67, chloroform) Analysis:

Calcd. for C ,,H O NS C, 46.95; H, 6.50; N, 2.74; S, 12.54;

Mol. Wt. 511.60.

Found: C, 46.64; H, 6.67; N, 2.73: S, 12.59; Mol. Wt. (Mass spec., M511.

Following the procedure of Parts B-1 and C-1 using the above compound(A-25) as the starting compound, there are obtained methyl7-deoxy-7(S)-(2,3- dihydroxypropylthio)-o1-thiolincosaminide and 7-deoxy-7(S)-(2,3-dihydroxypropylthio)-lincomycin hydrochloride.

The starting 2,3-dihydroxypropyl methyl sulfide is obtained by reacting1-chloro-2,3-dihydroxypropane with methanolic sodium methyl mercaptide.

EXAMPLE 26 7-Deoxy-7 (S)-(pheny1thio)lincomycin hydrochloride PartA-26a: Methyl N-acetyl-2,3,4-tri-O-acety1-7-deoxy-7(S)-(phenylthio)-a-thiolincosaminide Following the procedure ofPart A-1, substituting the methyl sulfide by methyl phenyl sulfide,methyl N- acetyl-2,3,4tri-O-acetyl-7(S)-(phenylthio)-athiolincosaminideis obtained as fine colorless needles from ethyl acetate having thefollowing characteristics:

m.p. 275276 (K 3.17, l ethanolzl water;1 ethyl acetatez3 cyclohexane)[11],, +164 (c, 0.53, ChCl Analysis:

Calcd. for C H ,O,,NS

C, 53.73; H, 6.08; N, 2.73; S, 12.49. Found: C, 53.87; H, 6.07; N, 2.48;S, 12.51.

Part A-26b: Alternate process Following the procedure of Example 13,substituting the methyl phenyl sulfide by benzyl phenyl sulfide the samecompounds are obtained. This process has the advantage of giving higheryields of the product.

Part B-26: Methyl 7-deoxy-7(S)-(phenylthio)-athiolincosaminide Followingthe procedure of Part B-l, there is obtained methyl7-deoxy-7(S)-(pheny1thio)-o1- thiolincosaminide as colorless flatneedles from methanol having the following characteristics:

[11],, +20l (c, 0.88, pyridine) Analysis:

Calcd. for C,,,H,,,O,NS,: I

C, 52.15; H, 6.71; N, 4.06; S, 18.56. Found: C, 52.50; H, 6.78; N, 4.24;S, 18.33.

Part C-26: 7-Deoxy-7(S)-(phenylthio)-1incomycin hydrochloride Followingthe procedure of Part C-l, there is obtained7-deoxy-7(S)-(phenylthio)-lincomycin hydrochloride as a colorlessamorphous solid having the following characteristics:

[01],, +81 (c, 0.63, H O) Analysis:

C, 53.86; H, 7.35; N, 5.24; S, 11.98; Cl, 6.63; v M. Wt. of free base498.69. Found (Corrected for 4.64% H O):

C, 54.08; H, 7.71; N, 5.55; S, 11.86; Cl, 6.49;

M. Wt. (Mass spec, M of free base) 498.

EXAMPLE 27 7(S)-(Benzylthio)-7-deoxylincomycin hydrochloride Part A-27:Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(benzylthio)-7-deoxy-a-thiolincosaminide Following the procedure ofExample 18, substituting the 2-(methylthio)ethanethiol by benzylsulfide, there is obtained methyl N-acetyl-2,3,4-tri'O-acetyl-7(S)-(benzylthio)-7-deoxy-a-thiolincosaminide.

Countercurrent distribution using as the solvent system l ethanolzlwater:0.5 ethyl acetate:3 cyclohexane yields this compound at a K valueof 1.38. It is obtained as flattened prisms from ethyl acetate-Skellysolve B having the following characteristics:

m.p. 21618 C.

. [01],, +161 (c, l.07,chloroform) Analysis:

Calcd. for C H O NS C, 54.63; H, 6.30; N, 2.66; S, 12.15. Found: C,55.02; H, 6.44; N, 2.94; S, 12.19.

Mol. Wt. Calcd. 527.64.

Mol. Wt. Found (Mass spec., M 527 Part 13-27:

Following the procedure of Part B-l using the above compound (A-27) asthe starting compound there is obtained methyl7(S)-(benzylthio)-7-deoxy-o1- thiolincosaminide as colorless plates frommethanol having the following characteristics:

[11],, +219 (c, 0.97, pyridine) Analysis:

Calcd. for C1 Hg504NS2I C, 53.45; H, 7.01; N, 3.90; S, 17.84;

Mol. Wt. 359.50.

Found: C, 53.37; H, 7.07; N, 4.12; S, (Mass spec., M") 359.

Part C-27:

Following the procedure of Part C-l using the above compound (B-27) asthe starting compound there is obtained7(S)-(benzylthio)-7-deoxylincomycin hydrochloride as a colorlessamorphous solid having the fol lowing characteristics:

[11],, +96.5 (c, 0.80, water) Analysis:

C, 54.67; H, 7.53; N, 5.10; Cl, 6.46 S, 11.68;

Mol. Wt. (free base): 512.72.

Found (Corrected for 2.74% water):

C, 54.89; H, 7.72; N, 4.83; CI, 6.28; S, 11.86; Mol. Wt. (Mass spec., M)512.

18.07; Mol. Wt.

EXAMPLE 28 1'-Demethyl-1'-(2-hydroxyethyl)-4'-depropyl-4'-cistrans-pentyl-7-deoxy-7(Smethylthio )lincomycin hydrochloride (Methyl6,7,8-trideoxy)-7-(methylthio )-6-cistransl -(2-hydroxyethyl)-4-pentyl-L-2-pyrro1idinecarboxamido)- 1 -thio-L-threo-a-D-ga1actooctopyranoiside hydrochloride) Part A-28: 1-Demethyl-l-carbobenzoxy-4'- depropy1-4'-cistrans-pentyl-7-deoxy-7(S)-(methylthio)lincomycin hydrochloride Following the procedure of Part C-lsubstituting the trans-propyl hygric acid by cistrans-l-carbobenzoxy-4-penty1-L-2-pyrrolidinecarboxylic acid using 2.2 mol. equivs. oftriethylamine, there is obtained 1-demethyl- 29l-carbobenzoxy-4-depropyl-4-cis- I trans-pentyl-7-deoxy-7(S)-(methylthio)-lincomycin hydrochloride.

lt separates from ethyl acetate as fine needles melting at 1589 C. whichare further characterized as follows:

[011 +1 18 (c, 0.84, chloroform) Analysis:

Calcd. for C H O N S C,'57.51; H, 7.58; N, 4.79; S, 10.97;

Mol. Wt. 584.78.

Found: C, 57.47; H, 7.51; N, 4.73; S, 11.19; Mol. Wt. (Mass spec., M584.

Part 13-28: 1'-Demethyl-b4-depropyl-4-cistranspentyl-7-deoxy-7(S)-(methylthio)-lincomycinhydrochloride A solution of the above carbobenzoxy compound (A-28) inethanol is hydrogenated in the presence of 10% palladium-on-carboncatalyst at a pressure of 50 lbs. per square inch hydrogen. The spentcatalyst is removed by filtration and the solvent evaporated to dryness.Residue is taken up in acetone and a stoichiometric amount of aqueous6N-hydrochloric acid is added. On the addition of ether,1-demethyl-4depropyl-4- cistrans-pentyl-7-deoxy-7(S)-(methylthio)-lincomycin hydrochloride (B-28) crystallizes as minute colorless needlesmelting at 183-4 C. (dec.) having the following chracteristics:

[04] +139 (c, 0.36, pyridine) Analysis:

Calcd. for C H O N S -HCl:

C, 49.31; H, 8.07; N, 5.75; Cl, 7.28; S, 13.17;

Mol. Wt. (free base) 450.65.

Found (Corrected for 4.31% water):

C, 48.96; H, 8.15; N, 5.78; Cl, 7.34; S, 12.9];

Mol. Wt. 450.

Part C-28: 1'-Demethyl-1'-(2-hydroxyethyl)-4-depropyl-4'-cistrans-pentyl-7-deoxy-7(S)- (methylthio)lincomycinhydrochloride The N-demethyl hydrochloride named above (8-28) isdissolved in ethyl alcohol, the solution cooled to 0 C., an excess ofethylene oxide added, the container sealed and heated for 2 hours at 100C. Removal of the volatile material gives a pale yellow syrupy residuewhich is dissolved in a mixture of chloroform and water and the pHadjusted to 10 with 50% aqueous sodium hydroxide. The organic layer isremoved and dried over anhydrous sodium sulfate. The chloroform isremoved and the residue chromatographed on silica gel using 1methanolzlO chloroform as the solvent system. Fractions corresponding toRf 0.31 are pooled, and evaporated to dryness. The residue is slurriedwith water and normal hydrochloric acid added to pH 4 at which time allthe solid is dissolved. The desired product is recovered as an amorphoussolid by lyophilization. It has the following characteristics:

[0:1 +88 (C, 0.82, water) Analysis:

C, 49.74; H, 8.16; N, 5.28; Cl, 6.68; S, 12.07;

Mol. Wt. (free base) 494.70.

Found (Corrected for 4.23% water):

C, 49.76; H, 7.99; N, 4.95; Cl, 6.76; S, 12.31;

Mol. Wt. (Mass spec., M of free base) 494.

EXAMPLE 29 Part A-29: Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxyphenylthio)-athiolincosaminide Following theprocedure of Part A-l8, substituting the ethyl trisulfide by allylZ-hydroxyphenyl sulfide, there is obtained methylNacetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxyphenylthio)-athiolincosaminide. Countercurrentdistribution in the system 1 ethanolzl waterzl ethyl acetate:2cyclohexane yields this compound at a K value of 1.54. It is isolated ascolorless rods from ethyl acetate having the following characteristics:

m.p. 2401 C.

[11] +154 (c, 0.83, chloroform) Analysis:

Calcd. for C H ,O NS

C, 52.16; H, 5.90; N, 2.65; S, 12.11;

Mol. Wt. 529.62.

Found: C, 52.23; H, 5.92; N, 2.72; S, 11.99; Mol. Wt. (Mass spec., M)529.

Following the procedures of Parts B-1 and C-l, there are obtained methyl7-deoxy-7(S)-(2- hydroxyphenylthio)-a-thiolincosaminide and 7-deoxy- 7(S2-hydroxyphenylthio)-lincomycin hydrochloride.

EXAMPLE 30 Methyl N-acetyl-2,3 ,4-tri-O-acetyl-7-deoxy-7(S 2-hydroxy-Z-methylethylthio)-a-thiolincosaminide Following the procedure of PartA-l substituting the methyl sulfide by 2-hydroxy-2-methylethyl methylsulfide but heating in an oil bath at C. for 24 hrs. there is obtainedmethyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxy-2-methylethylthio)-athiolincosaminide (K 1.0 in 1ethanol:1 water:l ethyl acetate:0.75 cyclohexane) as colorless prismsfrom ethyl acetate having the following properties:

[01],, +171 (c, 0.88, CHC1 Analysis:

Calcd. for C H O NS C, 48.47; H, 6.71; N, 2.83; S, 12.94;

M01. Wt. 495.60.

Found: C, 48.51; H, 6.71; N, 2.77; S, 12.72; Mol. Wt. (Mass spec., M*)495.

The starting 2-hydroxy-2-methylethyl methyl sulfide is prepared byheating 2-hydroxy-2-methylethyl bromide or 2-hydroxy-l-methylethylbromide or a mixture of the two with sodium methyl mercaptide inethanol.

By starting with 2-acetoxy-2-methylethyl methyl sulfide in place of the2-hydroxy-2-methylethyl methyl sulfide, methyl7(S)-(2-acetoxy-2-methylethylthio)-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-a-thiolincosaminide, m.p. 1992000 C.,is obtained.

Following the procedures of Parts B-1 and C-1 methylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxy-Z-methylethylthio)-a-thiolincosaminide and methyl7(S)-(2-acetoxy-2-methylethylthio)-N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-0z-thiolincosaminide are converted to methyl7-deoxy-7(S)-(2-hydroxy-2- methylethylthio)-a-thiolincosaminide and7-deoxy 7(- S)-(2-hydroxy-2-methylethylthio)-lincomycin.

EXAMPLE 31 7-Deoxy-7(S 3-hydroxypropylthio )-lincomycin hydrochloridePart A-3l: Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(3-acetoxypropylthio)-7-deoxy-a-thiolincosaminide Following theprocedure of Part A-l substituting the methyl sulfide by 3-acetoxypropylmethyl sulfide, there is obtained methylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(3-acetoxypropylthio)-7-deoxy-a-thiolincosaminide (K 1.0, 1 ethanolzlwater:1 ethyl acetate:2 cyclohexane) as colorless needles from ethylacetate:Skellysolve B having the following characteristics:

[01],, +178 (c, 0.94, CHCl Analysis:

Calcd. for C H ONS C, 49.15; H, 6.56; N, 2.61; S, 11.93. Found: C,49.31; H, 6.58; N, 2.68; S, 11.83.

Part B-3 1: Methyl 7-deoxy-7(S)-( 3-hydroxypropylthio)-a-thiolincosaminide Following the procedure of PartB-l substituting the methylN-acetyl-2,3,4-tri-Q-acetyl-7(S)-(methylthio)- a-thiolincosaminide bymethyl N-acetyl-2,3,4-tri-O- acetyl-7(S)-(3-acetoxypropylthio)-7-deoxy-athiolincosaminide, there is obtained methyl 7-deoxy-7(S)-(3-hydroxypropylthio)-a-thiolincosaminide as colorless needles fromwater having the following characteristics:

[011 +234 (c, 0.79, pyridine) Analysis:

Calcd. for C H O NS C, 44.01; H, 7.70; N, 4.28; S, 19.58. Found: C,43.93; H, 7.81; N, 4.45; S, 19.55.

Part C-3l: 7-Deoxy-7(S)-(3-hydroxypropylthio)lincomycin hydrochlorideFollowing the procedure of Part C-l substituting the methyl7-deoxy-7(S)-(methylthio)-athiolincosaminide by methyl 7-deoxy-7(S)-(3-hydroxypropylthio)-a-thiolincosaminide, there is obtained7-deoxy-7(S)-(3-hydroxypropylthio)lincomycin hydrochloride as anamorphous solid having the following characteristics:

[011 +110 (c, 0.82, H O) Analysis:

Calcd. for C H O N S HCl C, 48.77; H, 7.99; N, 5.42; Cl, 6.86; S, 12.40;

M01. Wt. of free base 480.68.

Found (Corrected for 2.86% water):

C, 49.11; H, 8.10; N, 5.88; S, 12.15; Cl, 6.82;

M01. Wt. (Mass spec., M") 480.

EXAMPLE 32 7(S)-(4-Acetoxybutylthio)-7-deoxylincomycin hydrochloridePart A-32: Methyl 7(S)-(4-acetoxybutylthio)-7- deoxy-a-thiolincosaminideFollowing the procedure of Part A-l substituting the methyl sulfide by4-acetoxybutyl methyl sulfide but heating at 110 C. for 20 hours, thereis obtained methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(4-acetoxybutylthio)-7-deoxy-a-thiolincosaminide (K 1.32, l ethanolzlwater:l ethyl acetate:2 cyclohexane) as fine rosettes of needles fromethyl acetateSkellysolve B having the following characteristics:

[a],, +171 (c, 0.88, CHCl Analysis: g

Calcd. for C H O NS C, 50.07; H, 6.76; N, 2.54; S, 11.62. Found: C,49.97; H, 6.86; N, 2.50; S, 11.35.

Part B-32: Methyl 7-deoxy-7(S)-(4-hydroxybutyl)-athiolincosaminideFollowing the procedure of Part B-l, there is obtained methyl7-deoxy-7(S)-(4-hydroxybutylthio)-athiolincosaminide as microcrystallineneedles from methanol having the following characteristics:

[04],, +218 (c, 0.41, H O) Analysis:

Calcd. for C H O NS C, 45.72; N, 7.97; N, 4.10; S, 18.78.

Found: C, 45.73; H, 8.13; N, 4.22; S, 18.33.

Part C-32: 7-Deoxy-7(S)-(4-hydroxybutylthio)- lincomycin hydrochlorideFollowing the procedure of Part C-l, there is obtained7-deoxy-7(S)-(4-hydroxybutylthio)-lincomycin hydrochloride as anamorphous solid having the following characteristics:

[11],, +105 (c, 0.96, H O) Analysis:

Calcd. for C22H4205N2S2-HC11 C, 49.74; H, 8.16; N, 5.28; Cl, 6.68; S,12.07;

M. Wt. of free base 494.70. Found (Corrected for 3.70% H O):

C, 49.58; H, 8.19; N, 5.23; CI, 6.48; S, 12.10;

M. Wt. (Mass spec., M of free base) 494.

EXAMPLE 33 Methyl N-acetyl-2,3,4-triO-acetyl-7(S)-(5-acetoxypentylthio)-7-deoxy-a-thiolincosaminide Following the procedureof Part A-l substituting the methyl sulfide by S-acetoxypentylmethyl'sulfide and heating at C. for 16 hrs., there is obtained methylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(5-acetoxypentylthio)-7-deoxy-a-thiolincosaminide having a K value of 1.94in 1 ethanol:l H O:1 ethyl acetate:2 cyclohexane and the followingcharacteristics as recrystallized from ethyl acetate-Skellysolve B.

m.p. l589 C. (needles) [011 +169 (c, 0.60, CHCl Analysis:

Calcd. for C H O NS C, 50.95; N, 6.95; N, 2.48; S, 11.34.

Found: C, 50.88; H, 6.98; N, 2.41; S, 11.22.

Following the procedures of Parts B-land C-2, there are obtained methyl7-deoxy-7(S)-(5- hydroxypentylthio)-a-thiolincosaminide and 7-deoxy-7(S)-(5-hydroxypentylthio)lincomycin hydrochloride.

EXAMPLE 34 Methyl N-acetyl-2,3 ,4-tri-O-acetyl-7( S)-( 2-acetoxycyclohexylthio )-7-deoxy-a-thiolincosaminide Following theprocedure of Part A-l substituting the methyl sulfide, by2-acetoxycyclohexyl methyl sulfide and heating at 100 C. for 16 hours,there is obtained methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(2-acetoxycyclohexylthio)-7-deoxy-a-thiolincosaminide. Countercurrentdistribution in the solvent system 1 3 to 6 ring members in the ring,and the acid addition salts thereof with the proviso that when X issulfur, R

tained as colorless needles from ethyl acetate having the followingcharacteristics:

m.p. 2056 C.

[04] +l53 (c, 0.64, CHCl Analysis:

Calcd. for C H O NS C, 51.97; H, 6.80; N, 2.43; S, 11.10;

Mol. Wt. 577.70.

Found: C, 51.82; H, 6.87; N, 2.29; S, 11.12;

Mol. Wt. (Mass spec., M") 577.

Following the procedure of Parts B-1 and C-l, there are obtained methyl7-deoxy-7(S)-[(2- hydroxycyclohexyl)thio]-a-thiolincosaminide and 7-deoxy-7(S)-[(2-hydroxycyclohexyl)thio]lincomycin hydrochloride.

1 claim:

1. A compound of the formula:

AcNH

OAC1

Alk

OAC1

wherein n is l; Alk is alkyl of not more than 4 carbon atoms, or Ac,OCHCH Ac, is selected from hydrogen and hydrocarbon carboxacyl containingnot more than 18 carbon atoms or halo-, nitro-, hydroxy-, aminocyano-,thiocyano or alkoxy-substituted hydrocarbon carboxacyls of not more than18 carbon atoms; Ac is selected from hydrogen, hydrocarbon carboxacyl asdefined above, and an L-2-pyrrolidinecarboxacyl group selected from L-2pyrrolidinecarboxacyl, N-methyl-L- 2-pyrrolidinecarboxacyl,N-ethyl-L-2-pyrrolidinecarboxacyl,N-(2-hydroxyethyl)-L-2-pyrrolidinecarboxacyl and forms thereofsubstituted in the 4-position with a group selected from lower alkyl andlower alkylidene; provided that when Ac is hydrogen, Ac, is hydrogen andwhen Ac is hydrocarbon carboxacyl, Ac, is hydrocarbon carboxacyl; R is asaturated aliphatic hydrocarbon radical of not more than 18 carbonatoms, an unsaturated aliphatic hydrocarbon radical of not more than 10carbon atoms, a cycloaliphatic hydrocarbon radical of not more than 10carbon atoms; an aromatic hydrocarbon radical of not more than 1 1carbon atoms, or an oxacarbocyclic aromatic or thiacarbocyclic aromatichydrocarbon radical of not more than 8 carbon atoms; XR is hydrogen or agroup wherein X is oxygen or sulfur and R is hydrogen, hydrocarboncarboxacyl containing not more than 18 carbon atoms or halo-, nitro-,hydroxy-, amino-, cyano-, thiocyano-, or alkoxysubstituted hydrocarboncarboxacyls of not more than 18 carbon atoms, lower alkyl, loweralkenyl, lower cycloalkyl, lower cycloalkenyl, lower alkoxyalkyl, loweralkylthioalkyl, phenyl, benzyl, furyl, furfuryl, thienyl, or thenyl; andwherein R and R when X is oxygen and R is alkyl, can be linked togetherto form an oxacycloalkyl of not more than 5 carbon atoms, having from isneither hydrogen, hydrocarbon carboxacyl contain ing not more thaneighteen carbon atoms nor halo-, nitro-, hydroxy-, amino-, cyano-,.thiocyano-, or alkoxysubstituted hydrocarbon carboxacyl of not morethan 18 carbon atoms.

2. A compound according to claim 1 in which Ac and Ac are acetyl and nis l.

3. A compound according to claim 2 in which Alk is methyl. 1

4. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(methylthio)-a-thiolincosaminide, a compound according to claim 1.

5. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(ethylthio)-a-thiolincosaminide, a compound according to claim 1.

6. Methyl N-acetyl-Z,3,4-tri-O-acetyl-7-deoxy-7(S)-(propylthio)-a-thiolincosaminide, a compound according to claim 1.

7. Methyl N-acetyl-2,3,4-tri-O-acetyl-7rdeoxy-7(S)-(isopropylthio)-a-thiolincosaminide, a compound according to claim 1.

8. Methyl N-acetyl-2,3,4-tri-O-acetyl 7-deoxy-7(S)'(cyclohexylthio)-a-thiolincosaminide, a compound-according to claim 1. y

9. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclopentylthio)-a-thiolincosaminide, a compound according to claim 1.1

l0. Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(butylthio)-7-deoxy-a-thiolincosaminide, a compound according toclaim 1. r

11. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-dedxy-7 (S)-(2-hydroxyethylthio)-a-thiolincosaminide, a compound according to claim1.

12. MethylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(tertbutylthio)-7-deoxy-a-thiolincosaminide,a compound according to claim 1. A

13. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(methylthio)ethyl-a-thiolincosaminide, a compound according to claim 1.

14. Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-[2-(tert.butylthio)ethylthio]-7-deoxy-athiolincosaminide, a compoundaccording to claim 1.

l5. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)- [(3-methylthio)propylthio]-a-thiolincosaminide, a compound according to claim 1.

16. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7( S)-(2-methylethylthio)-a-thiolincosaminide, a compound according to claim1.

17. Methyl N-acetyl-Z,3,4-tri-O-acetyl'7-deoxy-7(S)-(vinylthio)-a-thiolincosaminide, a compound according to claim 1.

l8. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(allylthio)-a-thiolincosaminide, a compound according to claim 1.

l9. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(propenylthio)-a-thiolincosaminide, a compound according to claim 1.

20. Methyl N-acetyl-Z,3,4-tri-O-acetyl-7-deoxy-7(S)-(phenylthio)-a-thiolincosaminide, a compound according to claim 1.

21. Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(benzylthio)-7-deoxy-a-thiolincosaminide, a compound according to claim1.

22. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(Z-hydroxyphenylthio)-a-thiolincosaminide, a compound according to claim1.

23. Methyl N-acetyl-Z,3,4-tri-O-acety'l-7-deoxy-7(S)-(2-hydroxy-2-methylethylthio)-a-thiolincosaminide, a compound accordingto claim 1.

24. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-acetoxyethylthio)-a-thiolincosaminide, a compound according to claim1.

25. Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(3-acetoxypropylthio)-7-deoxy-a-thiolincosaminide, a compound according toclaim 1.

26. Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(4-acetoxybutylthio)-7-deoxy-a-thiolincosaminide, a compound according toclaim 1.

27. A compound or an acid addition salt thereof according to claim 1wherein Ac and Ac are hydrogen, n is l and Alk is methyl, ethyl, or2-hydroxyethyl.

28. A compound or an acid addition salt thereof according to claim 1wherein Ac and Ac are hydrogen, n is l and Alk is methyl.

29. Methyl 7-deoxy-7(S)-(methylthio)-athiolincosaminide, according toclaim 1.

30. Methyl .7-deoxy-7( S ethylthio )-athiolincosaminide, according toclaim 1.

31. Methyl 7-deoxy-7(S)-(propylthio)-athiolincosaminide, according toclaim 1.

32. Methyl 7-deoxy-7(S)-(isopropylthio)-athiolincosaminide, according toclaim 1.

33. Methyl 7-deoxy-7(S)-(cyclohexylthio)-athiolincosaminide, accordingto claim 1.

34. Methyl 7(S)-(butylthio)-7-deoxy-athiolincosaminide, according toclaim 1.

35. Methyl 7(S)-(2-hydroxyethylthio)-7-deoxy-athiolincosaminide,according to claim 1.

36. Methyl 7-deoxy-7(S)-(2-methoxyethylthio)-athiolincosaminide,according to claim 1.

37. Methyl 7- deoxy-7(S)-(phenylthio)-athiolincosaminide, according toclaim 1.

38. Methyl 7(S)-(benzylthio)-7-deoxy-athiolincosaminide, according toclaim 1.

39. Methyl 7-deoxy-7(S)-(2-hydroxyphenylthio)-athiolincosaminide,according to claim 1.

40. Methyl 7-deoxy-7(S)-(3-hydroxypropylthio)-athiolincosaminide, acompound according to claim 1.

Methyl 7-deoxy-7(S)-(4-hyroxybutyl)-athiolincosaminide, a compoundaccording to claim 1.

42. A compound or an acid addition salt thereof according to claim 1wherein Ac is hydrogen and Ac is the acyl of anL-2-pyrrolidinecarboxylic acid and Alk is methyl, ethyl, or2-hydroxyethyl.

43. A compound or an acid addition salt thereof according to claim 42wherein the L-2- pyrrolidinecarboxylic acid is substituted in the 4-position by a lower alkyl or a lower alkylidene group.

44. A compound or an acid addition salt thereof according to claim 43 inwhich the l-position is substituted by a methyl, ethyl or 2hydroxyethylgroup and the 4-position by trans-propyl.

45. A compound or an acid addition salt thereof according to claim 1wherein Ac is hydrogen and Ac is the acyl of atrans-l-methyl-4-propyl-L-2- pyrrolidinecarboxylic acid, Alk is methyl.

46. 7-Deoxy-7(S)-(methylthio)lincomycin hydrochloride [Methyl6,7,8-trideoxy-7-(methylthio)-6- trans-( l-methyl-4-propyl-L-2-pyrrolidenecarboxamido l -thio-L-threo-a-D- galacto-octopyranosidehydrochloride, according to claim 1.

47. 7-Deoxy-7(S)-(ethylthio)-lincomycin hydrochloride, according toclaim 1.

48. 7-Deoxy-7(S)-(propylthio)-lincomycin hydrochloride, according toclaim 1.

49. 7-Deoxy-7(S)-(isopropylthio)-lincomycin hydrochloride, according toclaim 1.

50. 7(S)-(cyclohexylthio)-7-deoxylincomycin hydrochloride, according toclaim 1.

51. 7-Deoxy-7(S)-(butylthio)-lincomycin hydrochloride, according toclaim 1.

52. Methyl N-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-methoxyethylthio)-lincomycin hydrochloride, according to claim 1.

53. 7-Deoxy-7(S)-(2-hydroxyethylthio)-lincomycin hydrochloride,according to claim 1.

54. 7-Deoxy-7(S)-(Phenylthio)-lincomycin hydrochloride, according toclaim 1.

55. 7(S)-(benzylthio)-7-deoxylincomycin hydrochloride, according toclaim 1.

56. 7-Deoxy-7(S)-(2-hydoxyphenylthio)-lincomycin hydrochloride,according to claim 1.

57. 7-Deoxy-7(S)-(2-hyroxycyclohexylthio)lincomycin hydrochloride,according to claim 1.

58. l '-Demethyl-l '-carbobenzoxy-4'-depropyl-4'-cistranspentyl-7-deoxy-7(S)-(methylthio)lincomycin.

59. 1'-Demethyl-4'-depropyl-4'-cistrans-pentyl-7-deoxy-7(S)-(methylthio)lincomycin hydrochloride.

60. l-Demethyl-l -(2-hydroxyethyl)-4-depropyl-4'-cis-trans-pentyl-7-deoxy-7(S)-(methylthio)lincomy cin hydrochloride.

61. Methyl N-acetyl-2,3,4-tri O-acetyl-7(S)-(2-acetoxyethylthio)-7-deoxy-a-lincosaminide according to claim 1.

62. Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(5-acetoxypentylthio)-7-deoxy-a-thiolincosaminde according to claim 1.

63. Methyl N-acetyl-2,3,4-tri-O-acetyl-7(S)-(2-acetoxy-cyclohexylthio)-7-deoxy-a-thiolincosamirlide according to claim1.

64. A compound in accordance with claim 1 wherein R is selected from thegroup consisting of saturated aliphatic hydrocarbon radical of not morethan eighteen carbon atoms, unsaturated aliphatic hydrocarbon radical ofnot more than eighteen carbon atoms, cycloaliphatic hydrocarbon radicalof not more than ten carbon atoms, phenylene and benzylene; XR ishydrogen or a group wherein X is oxygen or sulfur and when X is oxygen,R is selected from the group consisting of hydrogen, lower alkyl, andhydrocarbon carboxacyl containing not more than eighteen carbon atoms,and when X is sulfur, R is selected from the group consisting of loweralkyl and lower alkoxyalkyl.

65. A compound in accordance with claim 64 wherein when X is sulfur, Ris lower alkyl.

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 inwhich Ac and Ac1 are acetyl and n is
 1. 3. A compound according to claim2 in which Alk is methyl.
 4. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(methylthio)-Alpha-thiolincosaminide, a compound according to claim
 1. 5. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(ethylthio)-Alpha-thiolincosaminide, a compound according to claim
 1. 6. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(propylthio)-Alpha-thiolincosaminide, a compound according to claim
 1. 7. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(isopropylthio)- Alpha-thiolincosaminide, a compound according to claim
 1. 8. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclohexylthio)- Alpha-thiolincosaminide, a compound according to claim
 1. 9. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(cyclopentylthio)- Alpha-thiolincosaminide, a compound according to claim
 1. 10. MethylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(butylthio)-7-deoxy-Alpha-thiolincosaminide, a compound according to claim
 1. 11. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxyethylthio)- Alpha-thiolincosaminide, a compound according to claim
 1. 12. MethylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(tert-butylthio)-7-deoxy- Alpha-thiolincosaminide, a compound according to claim
 1. 13. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(methylthio)ethyl- Alpha-thiolincosaminide, a compound according to claim
 1. 14. MethylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(2-(tert.butylthio)ethylthio)-7-deoxy-Alpha -thiolincosaminide, a compound according to claim
 1. 15. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-((3-methylthio)propylthio)-Alpha -thiolincosaminide, a compound according to claim
 1. 16. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-methoxyethylthio)- Alpha-thiolincosaminide, a compound according to claim
 1. 17. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(vinylthio)-Alpha-thiolincosaminide, a compound according to claim
 1. 18. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(allylthio)-Alpha-thiolincosaminide, a compound according to claim
 1. 19. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(propenylthio)- Alpha-thiolincosaminide, a compound according to claim
 1. 20. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(phenylthio)- Alpha-thiolincosaminide, a compound according to claim
 1. 21. MethylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(benzylthio)-7-deoxy- Alpha-thiolincosaminide, a compound according to claim
 1. 22. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxyphenylthio)- Alpha-thiolincosaminide, a compound according to claim
 1. 23. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-hydroxy-2-methylethylthio)-Alpha -thiolincosaminide, a compound according to claim
 1. 24. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-acetoxyethylthio)- Alpha-thiolincosaminide, a compound according to claim
 1. 25. MetHylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(3-acetoxypropylthio)-7-deoxy- Alpha-thiolincosaminide, a compound according to claim
 1. 26. MethylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(4-acetoxybutylthio)-7-deoxy- Alpha-thiolincosaminide, a compound according to claim
 1. 27. A compound oran acid addition salt thereof according to claim 1 wherein Ac and Ac1are hydrogen, n is 1 and Alk is methyl, ethyl, or 2-hydroxyethyl.
 28. Acompound or an acid addition salt thereof according to claim 1 whereinAc and Ac1 are hydrogen, n is 1 and Alk is methyl.
 29. Methyl7-deoxy-7(S)-(methylthio)- Alpha -thiolincosaminide, according toclaim
 1. 30. Methyl 7-deoxy-7(S)-(ethylthio)- Alpha -thiolincosaminide,according to claim
 1. 31. Methyl 7-deoxy-7(S)-(propylthio)- Alpha-thiolincosaminide, according to claim
 1. 32. Methyl7-deoxy-7(S)-(isopropylthio)- Alpha -thiolincosaminide, according toclaim
 1. 33. Methyl 7-deoxy-7(S)-(cyclohexylthio)- Alpha-thiolincosaminide, according to claim
 1. 34. Methyl7(S)-(butylthio)-7-deoxy- Alpha -thiolincosaminide, according toclaim
 1. 35. Methyl 7(S)-(2-hydroxyethylthio)-7-deoxy- Alpha-thiolincosaminide, according to claim
 1. 36. Methyl7-deoxy-7(S)-(2-methoxyethylthio)- Alpha -thiolincosaminide, accordingto claim
 1. 37. Methyl 7-deoxy-7(S)-(phenylthio)- Alpha-thiolincosaminide, according to claim
 1. 38. Methyl7(S)-(benzylthio)-7-deoxy- Alpha -thiolincosaminide, according toclaim
 1. 39. Methyl 7-deoxy-7(S)-(2-hydroxyphenylthio)- Alpha-thiolincosaminide, according to claim
 1. 40. Methyl7-deoxy-7(S)-(3-hydroxypropylthio)- Alpha -thiolincosaminide, a compoundaccording to claim
 1. 41. Methyl 7-deoxy-7(S)-(4-hyroxybutyl)- Alpha-thiolincosaminide, a compound according to claim
 1. 42. A compound oran acid addition salt thereof according to claim 1 wherein Ac1 ishydrogen and Ac is the acyl of an L-2-pyrrolidinecarboxylic acid and Alkis methyl, ethyl, or 2-hydroxyethyl.
 43. A compound or an acid additionsalt thereof according to claim 42 wherein the L-2-pyrrolidinecarboxylicacid is substituted in the 4-position by a lower alkyl or a loweralkylidene group.
 44. A compound or an acid addition salt thereofaccording to claim 43 in which the 1-position is substituted by amethyl, ethyl or 2-hydroxyethyl group and the 4-position bytrans-propyl.
 45. A compound or an acid addition salt thereof accordingto claim 1 wherein Ac1 is hydrogen and Ac is the acyl of atrans-1-methyl-4-propyl-L-2-pyrrolidinecarboxylic acid, Alk is methyl.46. 7-Deoxy-7(S)-(methylthio)lincomycin hydrochloride (Methyl 6,7,8-trideoxy-7-(methylthio)-6-trans-(1-methyl-4-propyl-L-2-pyrrolidenecarboxamido))-1-thio-L-threo- Alpha-D-galacto-octopyranoside hydrochloride, according to claim
 1. 47.7-Deoxy-7(S)-(ethylthio)-lincomycin hydrochloride, according to claim 1.48. 7-Deoxy-7(S)-(propylthio)-lincomycin hydrochloride, according toclaim
 1. 49. 7-Deoxy-7(S)-(isopropylthio)-lincomycin hydrochloride,according to claim
 1. 50. 7(S)-(cyclohexylthio)-7-deoxylincomycinhydrochloride, according to claim
 1. 51.7-Deoxy-7(S)-(butylthio)-lincomycin hydrochloride, according to claim 1.52. MethylN-acetyl-2,3,4-tri-O-acetyl-7-deoxy-7(S)-(2-methoxyethylthio)-lincomycinhydrochloride, according to claim
 1. 53.7-Deoxy-7(S)-(2-hydroxyethylthio)-lincomycin hydrochloride, according toclaim
 1. 54. 7-Deoxy-7(S)-(phenylthio)-lincomycin hydrochloride,accordiNg to claim
 1. 55. 7(S)-(benzylthio)-7-deoxylincomycinhydrochloride, according to claim
 1. 56.7-Deoxy-7(S)-(2-hydoxyphenylthio)-lincomycin hydrochloride, according toclaim
 1. 57. 7-Deoxy-7(S)-(2-hyroxycyclohexylthio)lincomycinhydrochloride, according to claim
 1. 58.1''-Demethyl-1''-carbobenzoxy-4''-depropyl-4''-cis-transpentyl-7-deoxy-7(S)-(methylthio)lincomycin. 59.1''-Demethyl-4''-depropyl-4''-cis-trans-pentyl-7-deoxy-7(S)-(methylthio)lincomycin hydrochloride. 60.1''-Demethyl-1''-(2-hydroxyethyl)-4''-depropyl-4''-cis-trans-pentyl-7-deoxy-7(S)-(methylthio)lincomycinhydrochloride.
 61. MethylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(2-acetoxyethylthio)-7-deoxy- Alpha-lincosaminide according to claim
 1. 62. MethylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(5-acetoxypentylthio)-7-deoxy- Alpha-thiolincosaminde according to claim
 1. 63. MethylN-acetyl-2,3,4-tri-O-acetyl-7(S)-(2-acetoxy-cyclohexylthio)-7-deoxy-Alpha -thiolincosaminide according to claim
 1. 64. A compound inaccordance with claim 1 wherein R1 is selected from the group consistingof saturated aliphatic hydrocarbon radical of not more than eighteencarbon atoms, unsaturated aliphatic hydrocarbon radical of not more thaneighteen carbon atoms, cycloaliphatic hydrocarbon radical of not morethan ten carbon atoms, phenylene and benzylene; XR3 is hydrogen or agroup wherein X is oxygen or sulfur and when X is oxygen, R3 is selectedfrom the group consisting of hydrogen, lower alkyl, and hydrocarboncarboxacyl containing not more than eighteen carbon atoms, and when X issulfur, R3 is selected from the group consisting of lower alkyl andlower alkoxyalkyl.
 65. A compound in accordance with claim 64 whereinwhen X is sulfur, R3 is lower alkyl.